PROCESS OF PRODUCING 6a, 10a-TRANS-6a,7,8,10a-TETRAHYDRODIBENZO (b,d)-PYRANS

ABSTRACT

This invention is directed to a process of producing (-)-1hydroxy-3-n-amyl-6,6,9-trimethyl-6a,10a-trans -6a,7,8,10atetrahydrodibenzo(b,d)-pyran and related pyrans from resorcinols, including intermediates therein. The pyrans produced by this invention possess psychotomimetic and analgesic activity.

United States Patent Petrzilka June 6,1972

[54] PROCESS OF PRODUCING 6A, 10A- TRANS-6A,7,8,10A- TETRAHYDRODIBENZO(B,D)-PYRANS [72] Inventor: Theodor Petrzilka, 6 Rigistrasse, Erlenbach21-! 8703, Switzerland [22] Filed: July 2, 1970 [21] Appl.No.: 52,105

Related U.S. Application Data [62] Division of Ser. No. 760,055, Sept.16, 1968, aban- UNITED STATES PATENTS 3,388,136 6/1968 Taylor et al..260/345.3

OTHER PUBLICATIONS Gaoni et al., J. Am. Chem. Soc., Vol. 86, pp. 16461647 Primary Examiner-John M. Ford Attorney-Granville M. Brumbaugh,Ellen M. Graves, Mark M. Donohue, John E. Dumaresq, Dana M. Raymond,John F. Neary, Jr., James N. Buckner, Frank W. Ford, Jr., Fredrick C.Carver, Richard H. Fuller, Jr., John W. Brumbaugh, George W. Whitney,Allen G. Weise and Francis J. Hone [57] ABSTRACT This invention isdirected to a process of producing()lhydroxy-3-n-amyl-6,6,9-trimethyl-6a, l Oa-trans-6a,7,810atetrahydrodibenzo(b,d)-pyran and related pyrans from resorcinols,including intermediates therein. The pyrans produced by this inventionpossess psychotomimetic and analgesic activity.

1 1 Claims, No Drawings PROCESS OF PRODUCING 6A, lA-'l'RANS-6A,7,8,1OA-TETRAHYDRODIBENZO (B,D)-PYRANS RELATED APPLICATIONS This application isa divisional application of co-pending application Ser. No. 760,055,filed Sept. 16, 1968, now abandoned.

BACKGROUND OF THE INVENTION 10 The crude resin obtained from theflowering tops of female Since the source of hashish or marihuana hasbeen from the extraction of this material from various varieties ofplants, it has long been desired to provide an economical means ofchemically synthesizing this material, thereby eliminating the necessityof isolating this material from its natural source.

SUMMARY OF THE INVENTION In accordance with this invention, it has beendiscovered that compounds of the formula:

8 5 6 CHs wherein R, is hydrogen, halogen, or alkyl containing from oneto 10 carbon atoms, can be synthesized from compounds of the formula:

(III) wherein X is a halogen and R is as above.

The compound of formula III is treated with potassium t-amylate in thepresence of an aromatic solvent to produce the compound of formula I.

In addition to producing the naturally occur-ing products of formula l-Aabove, which have known bactericidal, sedative, analgesic andpsychotomimetic properties, the process of this inventionproduces newand novel pyrans of the formula:

wherein R is hydrogen, halogen or alkyl containing from one to 10 carbonatoms with the proviso that when R is n-arnyl, R is not substituted inthe three-position of the dibenz0(b,d)-pyran ring. A preferred class ofcompounds of formula I-B are those compounds having the formula:

wherein R is selected from the group consisting of alkyl radicals havingfrom one to four carbon atoms, alkyl radicals having from six to 10carbon atoms, and halogen.

The novel compounds of formulas l-B and I-C, exhibit pyschotomimetic,analgesic, sedative and bactericidal properties in like manner as thenaturally occurring compound of formula I-A above.

DETAILED DESCRIPTION The numbering of the rings in compounds of theformulas I, I-A, I-B, II and III is shown for the purpose ofconvenience. As used throughout the application, the term alkylcomprehends both straight and branched chain alkyl groups containingfrom one to 10 carbon atoms such as methyl, ethyl, n-propyl, isopropyl,n-butyl, tert-butyl, n-heptyl, n-octyl, etc. In accordance with apreferred embodiment of this invention, R is an alkyl residue situatedin the three-position of the compound of formula I above. The termhalogen includes all four halogens, i.e., chlorine, bromine, fluorineand iodine with chlorine and bromine being preferred.

The compounds of formula I above, are useful as psychotomimetic agents,sedatives and analgesics. The compounds of formula I above are used inthe form of conventional pharmaceutical preparations which contain saidcompounds in connection with conventional pharmaceutical organic orinorganic carrier materials suitable for internal administration. Thepharmaceutical compositions containing the compounds of formula I abovecan be administered parenterally or orally, dosages can be adjusted toindividual requirements, for example, these compounds can beadministered in dosages of from about 0.1 mg./kg. to about 5 mgJkg. perday. These dosages can be administered in a single dosage form or individed dosage forms. The pharmaceutical compositions can contain suchconventional organic or inorganic inert carrier materials as water,gelatin, lactose, starch, mangesium stearate, talc, vegetable oils,gums, polyalkylene glycols, Vaseline or the like. The pharmaceuticalpreparations can be in the conventional solid forms such as tablets,dragees, suppositories, capsules or in conventional liquid form such assolutions, suspensions or emulsions. The pharmaceutical compositions canbe submitted to conventional pharmaceutical expedients such assterilization and/or can contain conventional pharmaceutical additivessuch as preservatives, stabilizing agents, wetting agents, emulsifyingagents, salts for adjusting the osmotic pressure, buffers or the like.They can also contain other therapeutically useful materials.

The compounds of formula II can be synthesized by condensing in thepresence of an acid agent, a resorcinol of the formula: H

wherein R is as above, with either 1,5,8-menthatriene which has theformula:

7 HO OH As examples of the compounds of formula IV above that can beutilized in the process of this invention are included resorcinol,S-ethyl resorcinol, 2-(3,5-dihydroxyph enyl) hexane,2-(3,5-dihydroxyphenyl)-3-methyl octane, S-n-propyl resorcinol, S-methylresorcinol (orcinol), S-n-pentyl resorcinol (olivetol), 5-(l-methylbutyl) resorcinol, S-n-hexylresorcinol, 5-(l-ethylbutyl)-resorcinol, 5-( l, l-dimethyl-butyl)- resorcinol,5-(l,Z-dimethylbutyl)-resorcinol, S-n-heptylresorcinol, 5-(l-methylhexyl)-resorcinol, 5-n-octylresorcinol, 5-(l-n-propylpentyl)-resorcinol, 5-( l-methyloctyI)-resorcinol and thelike.

Any of the isomers of (+)-p-methadienol-( l) of formula VI above whichare (+)-cis and (+)-trans-p-menthadienol-( l) as well as the racemicmixture thereof can be utilized in the process of this invention toproduce the compound of formula Iabove.

The condensation of compounds of the formula IV with compounds of theformulas V or Vl can be carried out in a conventional inert solvent.Among the preferred solvents are included aliphatic or aromatichydrocarbons such as petroleum ether, benzene, toluene, etc.;halogenated aliphatic or aromatic hydrocarbons such as methylenechloride, chloroform, carbon tetrachloride, chlorobenzene, etc.;nitrated hydrocarbons such as nitrobenzene, etc.; and ethers such asdiethyl ether, tetrahydrofuran, dioxan, etc. Among the otherconventional solvents which are preferred to be utilized in the processof this invention are included dimethylforrnamide, dimethylsulphoxide,or liquid sulphur dioxide.

The reaction to produce the compound of formula II above is carried outin the presence of any conventional organic or inorganic acid agents.Among the preferred acid agents which can be utilized in carrying outthe process of this invention are included Lewis acids such as borontrifluoride, zinc chloride, aluminum chloride, tin tetrachloride, etc.;mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoricacid, sulfuric acid, phosphoric acid, polyphosphoric acids, etc.; andorganic acids such as p-toluene sulphonic acid, methane sulphonic acid,formic acid, glacial acetic acid, trifluoroacetic acid, trichloroaceticacid, oxalic acid, maleic acid etc. Sulphur dioxide can be utilized asboth the acid medium and the organic solvent. Therefore, when liquidsulphur dioxide is utilized as the solvent medium, the reaction of thisinvention will take place without the addition of any other acid agent.

In carrying out the reaction to produce the compound of formula IIabove, temperature and pressure are not critical and this reaction canbe carried out at room temperature and atmospheric pressure. If desired,lower or elevated temperatures can be utilized. This condensationreaction is advantageously effected at a temperature of from about 0 C.to about 120 C. In a preferred embodiment of this invention, thereaction is particularly preferably carried out in the presence ofp-toluene-sulphonic acid in benzene by heating to a temperature of aboutC. for 2 hours under reflux conditions.

The compounds of formula III above are prepared from the compound offormula II above by treating the compound of formula II above with ahydrohalic acid in the presence of a metal halide In this reaction, thehalide group of the metal halide should be the same as the halide groupof the acid halide. The metal halide can be formed from any Group IImetal, Group III and Group IV metal of the periodic chart. Among themetal halides which can be utilized are included aluminum bromide,aluminum chloride, stannic chloride, boron trifluoride, magnesiumchloride, titanium chloride, ferric chloride, etc. The preferred metalhalide utilized in accordance with this invention is zinc chloride. Anyconventional hydrohalic acid such as hydrochloric, hydrobromic, etc canbe utilized. Generally, this reaction is carried out in the presence ofan inert organic solvent. Any conventional inert organic solvent can beutilized. The preferred solvents are the halogenated hydrocarbonsolvents such as methylene chloride. In carrying out this reaction,temperature and pressure are not critical, and this reaction can becarried out at room temperature and atmospheric pressure. If desired,elevated or lower temperatures can be utilized.

In accordance with a preferred embodiment of this invention, thecompound of the formula II above is converted to a compound of theformula III above by treating the compound of the formula II above withzinc chloride in a methylene chloride solution saturated with hydrogenchloride.

In accordance with this invention, compounds of formula III above whereR is a halo group such as bromine or chlorine are new and novelcompounds. In accordance with a preferred embodiment of this invention,R is a halo group substituted in the 3-position of the benzo(b,d)-pyranring of the compound of formula III above.

The conversion of compounds of the formula II above to compounds of theformula I above, is accomplished by treating the compounds of theformula III with potassium t-amylate in the presence of an inertaromatic hydrocarbon solvent. Any conventional aromatic hydrocarbonsolvent can be utilized. Among the preferred aromatic hydrocarbonsolvents are included toluene, benzene, xylene, etc. The preferredsolvent is benzene. In carrying out this reaction, temperature andpressure are not critical and this reaction can be carried out at roomtemperature and atmospheric pressure. If desired, elevated or reducedtemperatures and pressures can be utilized. I-Iowever, temperatures aslow as 0 C. and as high as C. can be utilized depending upon thefreezing and boiling point of the solvent. However, It is generallypreferred to carry out the reaction at a temperature of 50 to 70 C.

The following examples are illustrative but not limitative of thisinvention. All temperatures are in degrees centigrade. The etherutilized in the examples is diethyl ether. The pressure utilized in theexamples is expressed as mmHg.

EXAMPLE 1 A solution of 360 mg. of olivetol and 270 mg. of(:)-pmenthatriene-( 1,5,8) in 7 ml. of liquid sulphur dioxide is allowedto stand at room temperature for 24 hours in a sealed tube. The sulphurdioxide is thereupon evaporated off under a calcium chloride tube. Theoily residue is dissolved in diethyl ether. The ether solution isextracted once with dilute sodium hydrogen carbonate and dried oversodium sulphate. After evaporation of the ether, 633 mg. of a yellowresin remains. The yellow resin which is obtained, is chromatographed on20 g. of silica gel and upon elution with benzene and distillation athigh vacuum, 168 mg. of (i)-l-hydroxy-3-n-amyl-6,6,9- trimethyl-6a,lOa-trans-6a,7, l0, la-tetrahydrodibenz0(b,d pyran is obtained. The R.value of the tetrahydrodibenzopyran obtained is 0.46; boiling point140-l50 C/0.001 mmHg. (silica gel thin layer chromatogram inchloroform).

EXAMPLE 2 A mixture of 450 mg. of olivetol, 380 mg.(+)-cis-pmenthadien-(2,8)-ol-(l) and 58 mg. of p-toluenesulphonic acidmonohydrate in 25 ml. of benzene is boiled under reflux for 2 hours. Theresulting orange-yellow solution is cooled in an ice-water bath anddissolved in diethyl ether. The ether solution is immediately shakenonce with dilute sodium hydrogen carbonate solution and once with sodiumchloride solution. The almost completely decolorized ether solution isdried over sodium sulphate. After evaporation of the ether, 818 mg. of alight yellow oil remained. The resulting yellow oil is chromatographedon 35 g. of silica gel and upon elution with benzene and distillation athigh vacuum, 384 mg. of l-hydroxy-3n-amyl-6,6,9-trimethyl-6a,'l0a-trans-6a,7,10,1021-tetrahydrodibenzo(b,d)-pyran is obtained.

EXAMPLE 3 A mixture of 474 mg. of olivetol, 403 mg. of(+)-tra.ns-pmenthadien-( 2,8)-ol( l) and 80 mg. of p-toluenesulphonicacid monohydrate in 25 ml. of benzene is reacted in the manner ofExample 2. There resulted 900 mg. of a yellow oil. The resulting yellowoil waschromatographed on 35 g. of silica gel and upon elution withbenzene and distillation at high vacuum, 436 mg. of()-l-hydroxy-3n-amyl-6,6,9-trimethyl- 6a, 1 Oa-trans-6a,7, l O, lOa-tetrahydrodibenzo( b,d )-pyran was obtained having a R value (silicagel thin layer chromatogram in chloroform) of 0.51; and a boiling pointof l40-l50 C./0.00l mmHg.

EXAMPLE 4 A mixture of 2.6 g. 13.4 mMol) of 2-(3,5- dihydroxy-phenyl)hexane, 2.05 g. (13.4 mMol) of (+)trans-p-menthadien- (2,8)-ol-( 1) and260 mg. (1.35 mMol) of p-toluenesulphonic acid monohydrate in 60 ml. ofbenzene is boiled under reflux for 2 Va hours. The resulting orangesolution is cooled in an ice-water bath and dissolved in diethyl ether.The ether solution is immediately shaken once with a dilute sodiumhydrogen carbonate solution and once with a sodium chloride solution.The now almost completely colorless ether solution is dried over sodiumsulphate. After evaporation of the ether there remains 4.85 g. of alight yellow oil. The resulting oil is chromatographed on 130 g. ofsilica gel and upon elution with a l to l by volume mixture of hexaneand benzene and drying to constant weight, there is obtained()-l-hydroxy-3-[hexyl( 2 ]-6,6,9-trimethyl-6a, l 0a-trans-6a,7, 10, 10atetrahydrodibenzo(b,d)-pyran. After distillation under high vacuum theproduct has an R value (silica gel chromatogram in chloroform) of 0.58and a boiling point of 190 C./0.00l mml-lg.

EXAMPLE A mixture of 2.16 g. (9.15 mMol) of2-(3,5-dihydroxyphenyl)'-3-meth yl octane, 1.4 g. (9.2 mMol) of(+)-trans-pmenthadien-( 2,8)-ol-( l) and 175 mg. (0.92 mMol) of ptoluenesulphonic acid monohydrate in 60 ml. of benzene is heated under refluxfor 2 541 hours. The resulting solution is cooled with an ice-water bathand dissolved in diethyl ether. The ether solution is immediately shakenonce with a dilute sodium hydrogen carbonate solution and once with asodium chloride solution. The solution is then dried over sodiumsulphate and after evaportion of the ether there remains 3.4 g. of alight yellow oil. The resulting yellow oil is chromatographed on 70 g.of silica gel and upon elution with l to l by volume mixture of hexaneand benzene and drying to constant weight, 1 -hydroxy-3-[ 3-methyloctyl(2 ]-6,6,9-trimethyl- 6a,l0a-trans-6a,7,l0,10a-tetrzhydrodibenzo(b,d)-pyran is produced. Upondistillation under high vacuum this produce has an R; value (silica gelchromatogram in chloroform) of 0.55 and a boiling point of 190 C./0.00lmml-lg.

EXAMPLE 6 2.84 g. (20 mMol) of orcinol-monohydrate is mixed with 3.05 g.(20 mMol of (+)-trans-p-menthadien-(2,8)-ol-( l) in 50 ml. of benzeneand 0.39g(2 mMol) of p-toluene sulphonic acid monohydrate. This mixtureis heated at reflux for 2 hours. The resulting reaction solution isadded to 50 ml. of diethyl ether and extracted once with a dilute sodiumbicarbonate solution. The ether phase is dried over sodium sulphate andthe ether is evaporated. There results 5.6 g. of a yellow oil which ischromatographed on 180 g. of silica gel and eluted with benzene. Theeluted solution is distilled at high vacuum yielding 2350 mg. of()-l-hydroxy-3,6,6,9-tetramethyl-6a,lOa-trans-6a,7,10,10a-tetrahydrodibenzo(b,d)-pyran. This compound hasan R value of 0.48 and a boiling point of -140 C./0.00l mml-lg.

EXAMPLE 7 A solution of 0.427 g. (2.37 mMol) of olivetol and 0.356 g.(2.34 mMol) of (+)-trans-p-menthadien-(2,8 )-ol-( 1) in liquid sulphurdioxide is allowed to stand at room temperature for 70 hours in a sealedtube. Thereafter, the solvent medium is carefully distilled off. Theresidue is dissolved in 50 ml. of diethyl ether. The ether solution isextracted once with a dilute sodium bicarbonate solution. Afterextraction, the ether solution is dried and evaporated. The dry residue(0.74 g.), which is obtained is chromatographed on silica gel andeluted.

One obtains after distillation utilizing a high vacuum, 142 mg. of()-l-hydroxy-3-n-amyl-6,6,9-trimethyl-6a,lOa-trans- 6a,7,10,lOa-tetrahydrodibenzo(b,d)-pyran. This compound has an R value(silica gel thin layer chromatogram in chloroform) of 0.51 and a boilingpoint of l 50 C./0.00l mml-lg.

EXAMPLE 8 0.595 g. (3.3 mMol) olivetol is mixed with 0.502 g. (3.3 mMol)(+)-cis-p-menthadie n-(2,8)-ol-(l) in 8 ml. of liquid sulphur dioxide.This mixture is allowed to stand at room temperature for 120 hours in asealed tube. After working up the mixture in the manner described inExample 1, 1.085 g. of an oily residue is obtained. The oil ischromatographed over silica gel and eluted. Upon distillation in highvacuum, 215 mg. of ()-l-hydroxy-3-n-amyl-6,6,9-trimethyl-6a,10a-trans-6a,7,l0,l0a-tetrahydrodibenzo(b,d)-pyran is obtained. This compound hasan R value (silica gel thin layer chromatogram in chloroform) of 0.52and a boiling point of l40-l 50 C./0.001 mml-lg.

EXAMPLE 9 A mixture of 0.54 g. (3 mMol) ofolivetol, 0.46 g. (3 mMol) of(+)-trans-p-menthadien-(2,8)-ol-(1) and 0.5 ml. of trifluoro acetic acidin 50 ml. of benzene is refluxed for 5 hours. The resulting solution isworked up in the manner of Example 2 to yield 0.95 g. of a residue. Theresulting residue is chromatographed on silica gel and upon elution anddistillation at high vacuum yields 520 mg. of()-l-hydroxy-3-namyl-6,6,9-trimethyl-6a,10a-trans-6a,7,10,l0atetrahydrodibenzo(b,d)9pyran. This compound has an R; value (silica gel thin layerchromatogram in chloroform) of 0.52 and a boiling point of l40150C./0.001 mmHg.

EXAMPLE 10 A mixture of 2.2 g. (20 mMol) of crystalline resorcinol, 3.05g. (20 mMol) (+)-trans-p-menthadien-(2,8) -ol-( 1) and 0.4 g. (2 mMol)of p-toluene sulphonic acid monohydrate in 50 ml. of benzene is heatedunder refulx for 2 hours. The resulting solution is dissolved in 50 ml.of diethyl ether. The ether is extracted once with dilute sodiumbicarbonate solution. The ether phase is dried and evaporated. 5.1 g. ofa yellow oil is obtained. This oil is chromatographed on 250 g. ofsilica gel and eluded with benzene. After distilling off the benzeneunder high vacuum, there is obtained 778 mg. of1-hydroxy-6,6,9-trimethyl-6a,l0a-trans-6a,7,10,10atetrahydrodibenzo(b,d)-pyran.This compound has an R value (silica gel thin layer chromatogram inchloroform) of 0.35 and a boiling point of 155 C./0.00l mml-lg.

EXAMPLE 1 l A. Preparation of ()-l-hydroxy-3-n-amyl-6,6,9-trimethyl- 6a,1 a-trans-6a,7,8, l 0a-tetrahydro-dibenzo( b,d)-pyran 1.080 g. (3.1mMol) of oily ()-1-hydroxy-3-n-amyl-9- chloro-6,6,9-trimentyl-6a,l0a-trans-6a,7,8,9,10,10a-hexahydro-dibenzo(b,d)-pyran is dissolved in15 m1. of absolute benzene. The resulting solution is added dropwiseunder stirring and under an atmosphere of argon to a 10 ml. solution ofl-M potassium t-amylate in absolute benzene which is cooled to 5 C.After the dropwise addition, the yellow reaction solution is heated formin. at 65 C. and then cooled with ice. After the solution is cooled,carbon dioxide is fed into the solution for approximately 30 minutescausing a partial decolorization of the solution. The solution ispartitioned between 80 ml. of ether and 80 ml. of ice water, the pH ofthe solution being neutralized to 7 by addition of a sodium bicarbonatesolution. The ether phase is dried over sodium sulphate and evaporated.After drying in high vacuum at 0.001 mml-lg there remains 970 mg.()-l-hydroxy-3-n-amyl-6,6,9trimethyl-6a,l0a-trans-6a,7,8,10a-tetrahydro-dibenzo(b,d)- pyran. [a]=l5(),5 (c=O.53/CHCl B. Preparation of ()-1-hydroxy-3-n-amyl-9-chloro-6,6,9-trimethyl-6a,10a-trans-6a,7,8,9,10,10a-hexahydrodibenzo(b,d)-pyran The l-hyd roxy-3-n-amyl-9-chloro-6,6,9-trimethyl-6 a, l 0a-trans-6a,7,8,9, lO, l 0a-hexahydro-dibenzo(b,d)-pyran used as the starting product ismanufactured as follows:

A solution of 1.046 g. (3.3 mMol) of oily(-)-l-hydroxy-3-n-amyl-6,6,9-trimethyl-6a, l0a-trans-6a,7,10,10a-tetrahydrodibenzo(b,d)-pyran which has been dried in high vacuum in ml. of absolutemethylene chloride is treated with 300 mg. of anhydrous zinc chloride.The colorless mixture is saturated with hydrogen chloride at 0 in adried apparatus and closed overnight at room temperature and allowed toreact with stirring. All of the oil has gone into solution after 15hours. The now deep yellow solution has added thereto 80 ml. ofmethylene chloride. After addition, this mixture is treated once with 80ml. of ice-water and then with sodium bicarbonate solution up toincipient precipitation of zinc hydroxide. After this treatment, themixture is extracted once with 50 ml. of water. The almost colorlessmethylene chloride phase is dried over sodium sulphate and evaporated atroom temperature. After drying in high vacuum, there is produced 1.120g. of oily ()-l-hydroxy-3-n-amyl-9-chloro-6,6,9-trimethyl-6 a, l0a-trans-6a,7,8,9, l 0, l 0a-hexahydro-dibenzo( b,d)-pyran. [a],, =78,5(c=0,28 in chloroform) EXAMPLE 12 1.00 g. of()-l-hydroxy3-[hexyl(2)]-9-chloro-6,6,9-trimethyl-6a,10a-trans6a,7,8,9,10,IOa-hexahydrodibenzo(b,d)-pyran is dissolved in 10 ml. of absolute benzene.

This solution is added dropwise under an atmosphere of argon to 10 ml.of l-M potassium t-amylate in absolute benzene, cooled to a temperatureof 5. After this dropwise addition, the resulting yellow solution isheated for 15 min. at 65 C. and then cooled wit ice. After cooling,carbon dioxide is fed into the solution for approximately 30 minutes,causing a partial decolorization of the solution. The solution is thenpartitioned between ml. of ether and 80 m1. of ice-water, the pH of thesolution being neutralized to 7 by addition of a sodium bicarbonatesolution. The ether phase is dried over sodium sulphate and evaporated.After drying in high vacuum at 0.001 mm., there resulted 0,90 g()-l-hydroxy-3-[hexyl(2)]-6,6,9-trimethyl-6a,l0a-trans-6a,7,8,10a-tetrahydro-dibenzo(b,d)- pyran.[a],,"=146 (c=0,46 in ethanol).

The ()-l-hydroxy-3-[hexyl(2)]-9-chloro-6,6,9-trimethyl-6a,l0a-trans-6a,7,8,9,10,10a-hexahydro-dibenzo(b,d)-pyran used as astarting material is manufactured according to the procedure in Example1 l-B from ()-l-hydroxy-3-[hexyl( 2)]-6,6,9-trimethyl-6a,l0a-trans-6a,7,10,10a-tetrahydrodibenzo(b,d)-pyran,by treatment with zinc chloride and hydrochloric acid in methylenechloride. This product exhibits the following characteristic data:[04],, -73.0 (c 2.3 in chloroform).

EXAMPLE l3 l -hydroxy-3-]3-methyl octyl( 2)]-9-chloro-6,6,9- trimethyl6a,l0a-trans-6a,7,8,9,10,10a-hexahydro- EXAMPLE 14 300 mg. of oily()-1-hydroxy-3[2-methylhexyl-(2)-9-chloro-6,6,9-trimethyl-6a,lOa-trans-6a,7,8,9,10,10a-hexahydro-dibenzo(b,d)-pyran is dissolved in 5 ml. of absolute benzene. The thus obtainedsolution is added dropwise under constant stirring to 5 ml. of asolution of l-M potassium-tamylate dissolved in benzene. During thedropwise addition, the solution of potassium-t-amylate is maintainedunder an atmosphere of argon. After this addition, a dark red solutionis obtained. The resulting mixture is heated to 65 C. for 15 minutes,then cooled with ice and at this temperature, carbon dioxide is bubbledinto the solution for approx. 30 minutes. A partial decolorization ofthe solution occurs after this addition. After this addition, thesolution is extracted with ether. The ether phase is dried andevaporated. After drying in high vacuum at 0.001 mml-lg for 12 hours at20 C. there remains 271 mg. of ()-l-hydroxy-3[2-methylhexyl-(2)]-6,6,9-trimethyl-6a,l0a-trans-6a,7,8,10a-tetrahydro-dibenzo(b,d)- pyran. [a],,=17l.3(c=O.29 in chloroform).

The starting material ()-l-hydroxy-3-[2-methylhexyl-(2)]-9-chloro-6,6,9-trimethyl-6a,l0a-trans-6a,7,8,9,10,10a-hexahydrodibenzo(b,d)-pyranis prepared by the following procedure:

A mixture of 350 mg. of 2-( 3,5-dihydroxyphenyl)-2-methylhexane, 260 mg.(+)-trans-p-menthadien-( 2,8 )-ol-( 1) in 20 ml. of benzene is boiledunder reflux with 40 mg. of p-toluene sulphonic acid monohydrate for 2 Ahours. The reaction solution is thereafter cooled with ice. A smallamount of an aq ueous solution of sodium bicarbonate is added to thecooled reaction solution. The condensation product is extracted from thereaction solution with diethyl ether. The extract is dried andevaporated. After drying and evaporating, 640 mg. of a yellow oilremains. The yellow oil, which is obtained, is chromatographed on 20 g.of silica gel. Upon elution with benzene and distillation at high vacuumthere is obtained 535 mg. of l -hydroxy-3-[2-methylhexyl-( 2)]-6,6,9-trimethyl-6a,10atrans-6a,7,l0,10a-tetrahydro-dibenzo(b,d)-pyran. The R value of thetetrahydro-dibenzo pyran obtained is 0.59 (silica gel thin layerchromatogram in chloroform). The boiling point of this compound is 170C./0.00l mml-lg.

330 mg. of oily ()-l-hydroxy-3-[2-methylhexyl-(2)]-6,6,9- trimethyl-6a,10a-trans-6a,7, l 0, la-tetrahydro-dibenzo(b,d)- pyran is dissolved in25 ml. of absolute methylene chloride. To this solution there is added100 mg. of anhydrous zinc chloride. The mixture is saturated withhydrogen chloride at 0 C. The apparatus containing this mixture isclosed and the saturated mixture is allowed to react overnight while itis maintained under constant stirring and at room temperature. Afterthis period, the reaction solution is diluted with methylene chlorideand then treated with ice water. After treating with ice water, sodiumbicarbonate solution is added to the mixture in an amount up to theincipient precipitation of the zinchydroxide. The methylene chloridephase is dried and evaporated. After drying in high vacuum, 0.001 mmHg.at 20 C. for 12 hours, there remains 362 mg. of (-)-lhydroxy- 3-[2-methylheXyl-( 2) ]-9-chloro-6,6,9-trimethyl-6a, 1 Oa-trans- 6a,7,8,9,l 0, l 0-hexahydro-dibenzo( b,d)-pyran. This pyran has an R, value(silica gel thin layer chromatogram in chloroform) of 0.63 and [(11=70.5 0.69 in chloroform).

EXAMPLE 15 A solution containing 140 mg. (-)-l hydroxy-3,9-dichloro-6,6,9-trimethyl-6a,l0a-trans-6a,7,8,9,10,10a-hexahydrodibenz0(b,d)-pyranin ml; of absolute benzene is added dropwise under an atmosphere ofargon to a 2 ml. solution of l-M potassium-t-amylate in absolutebenzene. The solution of potassium-t-amylate is maintained at 5 C. andconstantly stirred during the addition. After the addition is complete,the mixture is warmed to 65 C. for 15 minutes. The resulting orangesolution is cooled with ice and carbon dioxide is subsequently bubbledtherein for approximately 30 minutes-During the addition of the carbonicacid, decolorization of the solution occurs. Thereafter, the solution isextracted with ether. The ether extract is neutralized to a pH of 7 bythe addition of a sodium bicarbonate solution. The ether phase is driedover the sodium sulfate and evaporated. After drying in high vacuum at0.001 mml-lg there is produced 123 mg. of()-lhydroxy-3-chloro-6,6,9-trimethyl-6a, l 0a-trans 6a,7,8, l0atetrahydro-dibenzo(b,d)-pyran. This pyran has an R,- value of 0.33(silica gel thin layer chromatogram in chloroform) and [a],, -l66.2 (c0.35 in chloroform).

The starting material ()-l-hydroxy-3,9-dichloro-6,6,9- trimethyl-6a, l0a-trans-6a,7,8 ,9,10,l0a-hexahydrodibenzo( b,d )-pyran is produced bythe following procedure.

280 mg. of S-chloro-resorcinol is mixed with 300 mg. of(+)-trans-p-menthadien-(2,8)-ol-(1) dissolved in 20 ml. of benzene. Thismixture is refluxed for 2 hours with 40 mg. of ptoluene-sulphonic acidmonohydrate. Thereafter, the solution is cooled in ice. After coolingthe solution in ice, diethyl ether and a dilute sodium bicarbonatesolution are added thereto. The ether phase which results is dried andevaporated. The resulting residue is chromatographed on 30 g. of silicagel and upon elution with benzene and distillation at high vacuum thereis obtained 130 mg. of ()-l-hydroxy-3-chloro-6,6,9- trimethyl-6a, l0a-trans-6a,7, l 0, l 0a-tetrahydro-dibenzo(b,d)- pyran. This pyran hasa boiling point of 170 C./0.00l mmHg and an R, value (silica gel thinlayer chromatogram in chloroform) of 0.35; [01],, -278 (c 0.13 inchloroform).

150 mg. of (-)-l-hydroxy-3chloro-6,6,9 trimethyl-6a,10atrans-6a,7,10, l0a-tetrahydro-dibenzo( b,d)-pyran dissolved in 20 ml. of absolutemethylene chloride has 50 mg. of anhydrous zinc chloride added thereto.The resulting mixture is saturated with hydrogen chloride at 0 C. Thissaturated mixture is allowed to remain overnight at room temperature.The

resulting yellow solution is diluted with methylene chloride. 5 Thediluted solution is treated once with sodium bicarbonate solution in anamount up to the incipient precipitation of zinc hydroxide. Followingthe extraction, the resulting organic phase is dried and evaporated.After drying at high vacuum, 171 mg. of()-l-hydroxy-3,9-dichloro-6,6,9-trimethyl-6a,l0 a-trans-6a,7,8,9, l0,l0a-hexahydro-dibenzo(b,d )-pyran is obtained.

EXAMPLE 16 790 mg. of ()-l-hydroxy-3,6,6,9-tetramethyl-9chloro-6a,l0a-trans-6a,7,8,9,10,l0a-heXahydro-dibenzo(b,d)-pyran dissolved inml. of absolute benzene is added dropwise to a solution of 10 ml. of l-Mpotassium t-amylate in absolute benzene. This addition is carried outunder an atmosphere of argon while the potassium t-amylate solution isconstantly stirred and cooled by means of ice water. After the addition,the reaction solution is heated for 15 min. to a temperature of from6570 C. After cooling with ice, carbon dioxide is bubbled into thesolution for approximately 30 minutes. The mixture is partitionedbetween ether and ice water. The pH of the mixture is neutralized to 7by the addition of a sodium bicarbonate solution. The ether phase isdried and distillation under high vacuum produces 690 mg. of()-l-hydroxy-3,6,6,9- tetramethyl-6a, l Oa-tetrahydro-dibenzo(b,d)-pyran. This product is in the form of a yellow oil with an R value(silica gel thin layer chromatogram in chloroform) of 0.46 and a boilingpoint of 160 C./0.00l mmHg [01],, -229 (c =0.4/CHClb3).

The starting material ()-l-hydroxy-3,6,6,9-tetramethyl-9- chloro-6a, l0a-trans-6a,7,8 ,9, 10,10a-hexahydrodibenzo(b,d)-pyran is produced inthe manner of part B of Example l 1 from()-l-hydroxy-3,6,6,9-tetramethyl-6a,10atrans-6a,7, 10, lOa-tetrahydrodibenzo(b,d)-pyran. This starting material has [a] =98.4(c= 0.25/CHCl Iclaim:

l. A process for preparing a dibenzo-pyran of the formula:

wherein R, is hydrogen, halogen, or alkyl containing from one to 10carbon atoms, comprising treating in an inert aromatic solvent, acompound of the formula:

X CH:

wherein X is a halogen and R is as above, with potassium tamylate.

5. The process of claim 1 wherein said solvent is benzene.

wherein R is hydrogen, halogen, or alkyl containing from one to carbonatoms, comprising treating a compound of the formula:

wherein R is as above, with a metal halide in an inert halogenatedhydrocarbon solvent, wherein said solvent is saturated with a hydrohalicacid having the same halo group as the halo group of said metal halideto form a halo-dibenzo-pyran and treating the halodibenz0-pyran withpotassium t-amylate in an aromatic hydrocarbon solvent to form said6a,7,8,l 0atetrahydrodibenzopyran.

8. The process of claim 7 wherein said metal halide is zinc chloride andthe halogenated hydrocarbon solvent is methylene chloride saturated withhydrochloric acid.

9. The process of claim 7 wherein said metal is a Group ll, Group ill orGroup IV metal. I

10. The process of claim 7 wherein R, is n-amyl substituted in thethree-position of the dibenzopyran ring.

11. The process of claim 7 wherein R is methyl.

@2 3 v UNITED STATES PATENT OFFICE @ER'HFKCATE 0F CUREE'HON Patent No.3,668,22 Q 1 D d September 6, 1972 Inventor) Theodor Petrzilka It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

I First page, second column, line 5, change "Ellen" to Eben line 6,Change "M. Donohue" to -'N. Donohue Col. 3 line 37, change "CH" to CHCol. 6, line 12, change "tetrzhydrodi enz o to tetrahydrodibenzo 5 Col.7, line 2, change "(b,d)9pyran" to (b,d')-pyran Col. 7 line 2 7 change"trimentyl" to trimethyl Col. 8 line change "wit" to with Col. 8 line37, change "methylcotyl" to methyloctyl change "-methyloctyl(a-trans-"to lOa-trans- 99M Change y (2)-9-" to [2-methylhexyl-(2) 1-9- Col. 9,line 27, change F'lO-hexahydro" to lOa-heXahydro--; C01. 10 line 15,change "9chloro-" to 9c hloro C01. 10 line29, after "lOa-" inserttrans6a,7,8,lOa- Col. 10, line 33, change "=o.u/cHc1b3).!' to =O. l/CHCl"Col. 10, line 50, lowermost inside line missing from lef benzene ringof formula;

Col. 10, line 65, number 6 missing in lower right benzene-ring; Col. 11,line 10, number 6 missing in lower right benzene ring;

C01. 11 line 2 number 6 missing in lower right benzene ring.

Signed and sealed this 9th day of January 1973.,

(SEAL) Attest': I

EDWARD M.FLETGHER,JR, ROBERT GOT'ISCHALK J Attesting OfficerCommissioner of Patents

2. The process of claim 1 wherein said treating step is carried out byheating to a temperature of from 50* to 70* C.
 3. The process of claim 1wherein X is chlorine.
 4. The process of claim 1 wherein R1 is n-amyl.5. The process of claim 1 wherein said solvent is benzene.
 6. Theprocess of claim 1 wherein said solvent is toluene.
 7. The process ofpreparing a 6a,7,8,10a-tetrahydro-dibenzo-pyran of the formula:
 8. Theprocess of claim 7 wherein said metal halide is zinc chloride and thehalogenated hydrocarbon solvent is methylene chloride saturated withhydrochloric acid.
 9. The process of claim 7 wherein said metal is aGroup II, Group III or Group IV metal.
 10. The process of claim 7wherein R1 is n-amyl substituted in the three-position of thedibenzopyran ring.
 11. The process of claim 7 wherein R1 is methyl.